The development of new strategies and agents that provide for and enhance the passage of drugs and probes across biological barriers is a goal of unsurpassed significance in research, imaging, diagnostics, and therapy. Many potential drug candidates are abandoned during development simply because they do not possess the proper physical properties needed for formulation and to reach their targets. Other drug candidates are not even pursued because they are perceived to have problematic physical properties. Collectively, this restricts the universe of possible drug candidates to the limited few with optimal physical properties. For these drug candidates and more generally for many research tools, therapeutic leads and diagnostic agents, improved and highly effective delivery strategies are necessary.
The HIV Tat 9-mer (RKKRRQRRR), a polar (oligocationic) peptide, can cross non-polar cell membranes as a function of the number and spatial array of its guanidinium groups. Such agents, dubbed “guanidinium-rich molecular transporters”, are proposed to act as physical property “chameleons”, transitioning from polar oligocations to less polar, cell-penetrating complexes as they engage cell-surface anions in electrostatic and bifurcated hydrogen-bonding interactions. Compositionally diverse guanidinium-rich scaffolds, including peptoids, spaced peptides, oligocarbamates, dendrimers, and oligocarbonates are able to efficiently enter cells, including guanidinium-rich modified10-12 and cyclic peptides13,14, peptide nucleic acids,15 and transporters resulting from the oligomerization of guanidinium-containing monomers such as norbornenes, methacrylamides, and cyclic disulfides. These transporters can enhance the passage of numerous cargos including small molecules, peptides, and oligonucleotides, across multiple biological barriers including the cell wall of algae.